Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE(2) Cascade
Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE(2) Cascade
复制标题
内皮细胞中雷帕霉素复合物 1 的哺乳动物靶标对 YAP 的调节通过 COX-2/mPGES-1/PGE(2) 级联控制血压。
DOI：
10.1161/hypertensionaha.119.12834
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发表时间：
2019
期刊：
影响因子：
8.3
通讯作者：
Ai Ding
中科院分区：
文献类型：
--
作者：
Yao Liu;He Jinlong;Li Bochuan;Yan Meng;Wang Hui;Tan Lu;Liu Mingming;Lv Xue;Lv Huizhen;Zhang Xu;Chen Chen;Wang Daowen;Yu Ying;Huang Yu;Zhu Yi;Ai Ding
内皮细胞通过产生舒张和收缩因子来调节血管张力，以控制局部血流。高血压是mTORC 1（雷帕霉素复合物1的哺乳动物靶标）抑制剂的常见副作用。然而，内皮mTORC 1在高血压中的作用仍然是难以捉摸的。本研究旨在探讨内皮细胞mTORC 1在血管紧张素II（angiotensin II，Ang II）诱导的高血压中的作用及其机制。血管紧张素II在体外和体内均可增加内皮mTORC 1活性。在Ang II输注前后，Tie-2-Cre介导的mTOR（哺乳动物雷帕霉素靶蛋白;Raptor）异质性缺陷（Tie 2Cre-RaptorKD）小鼠的血压均高于对照小鼠。乙酰胆碱诱发的肠系膜动脉内皮依赖性舒张功能在Tie 2Cre RaptorKD小鼠中受损。用吲哚美辛或特异性考克斯（环氧合酶）-2抑制剂NS-398治疗，而不是L-NG-硝基精氨酸甲酯治疗，可以减少Raptorflox/−小鼠的内皮依赖性舒张，其程度与Tie 2Cre-RaptorKD小鼠相似。代谢组学分析显示，Tie 2Cre-RaptorKD小鼠血浆中前列腺素E2的含量在有或没有血管紧张素II输注的情况下降低。在内皮细胞中，雅普（yes相关蛋白）蛋白水平的降低与siRNA介导的RPTOR缺陷是自噬依赖性的，并且转录调节考克斯-2和mPGES-1（微粒体前列腺素E合成酶-1）的表达。因此，雅普在内皮细胞中的过表达增强了考克斯-2和mPGES-1的mRNA和蛋白水平，并逆转了Tie 2Cre-RaptorKD小鼠的内皮功能障碍和高血压。目前的结果表明，在内皮细胞中抑制mTORC 1活性减少前列腺素E2的产生，并通过减少YAP介导的考克斯-2/mPGES-1的表达引起高血压。
Endothelial cells regulate vascular tone by producing both relaxing and contracting factors to control the local blood flow. Hypertension is a common side effect of mTORC1 (mammalian target of rapamycin complex 1) inhibitors. However, the role of endothelial mTORC1 in hypertension remains elusive. The present study aimed to determine the role of endothelial mTORC1 in Ang II (angiotensin II)–induced hypertension and the underlying mechanism. Endothelial mTORC1 activity was increased by Ang II both in vitro and in vivo. Blood pressure was higher inTie-2-Cre–mediated regulatory associated protein of mTOR (mammalian target of rapamycin;Raptor) heterozygous-deficient (Tie2Cre-RaptorKD) mice than control mice both before and after Ang II infusion. Acetylcholine-evoked endothelium-dependent relaxation of mesenteric arteries was impaired inTie2Cre-RaptorKDmice. Treatment with indomethacin or a specific COX (cyclooxygenase)-2 inhibitor, NS-398, but not L-NG-nitroarginine methyl ester reduced endothelium-dependent relaxation inRaptorflox/−mice to a similar extent as inTie2Cre-RaptorKDmice. Metabolomic profiling revealed that the plasma content of prostaglandin E2was reduced inTie2Cre-RaptorKDmice with or without Ang II infusion. In endothelial cells, reduction of the protein level of YAP (yes-associated protein) withsiRNA-mediatedRPTORdeficiency was autophagy dependent and transcriptionally regulated the expression of COX-2 and mPGES-1 (microsomal prostaglandin E synthase-1). Hence, overexpression of YAP in endothelial cells enhanced the mRNA and protein levels of COX-2 and mPGES-1 and reversed the endothelial dysfunction and hypertension inTie2Cre-RaptorKDmice. The present results demonstrate that suppression of mTORC1 activity in endothelial cells reduces prostaglandin E2production and causes hypertension by reducing YAP-mediated COX-2/mPGES-1 expression.